This invention relates to cephalosporin antibiotics. In particular it relates to cephalosporin antibiotics directly substituted in the 3-position of the cephem ring system with a divalent sulfur atom also bonded to a 5- or 6-membered heterocyclic ring, a C.sub.1 to C.sub.4 lower alkyl group, or with a phenyl or substituted phenyl group.
Since the discovery of cephalosporin C as well as the further discovery that the .alpha.-amino adipoyl side chain thereof could be cleaved to provide the cephalosporin nucleus, a large number of different cephalosporin antibiotics have been synthesized and described. In these syntheses, a large number of structural variations have been made in the 7-position side chain by the acylation of the 7-amino cephalosporin nucleus. Many other variations, and oftentimes in combination with variations in the side chain, have been made in the 3'-position of the cephalosporin nucleus. For example, the acetoxy group of the acetoxymethyl substituent in the 3-position of the cephalosporin nucleus has been substituted by a wide variety of groups such as the preparation of the C.sub.A compounds with pyridines, the displacement of the acetoxy group with sulfur nucleophiles as well as with other groups.
Cephalosporin antibiotics having a methyl group in the 3-position of the cephem ring, the deacetoxycephalosporanic acids, have been synthesized by the now well known penicillin sulfoxide rearrangement discovered by R. B. Morin, et al., U.S. Pat. No. 3,275,626. Until recently, all of the known cephalosporin antibiotics possessed the structural feature of either a 3-methyl group, a substituted 3-methyl group or a hydrogen at the 3-position of the cephem ring system. Recently, however, R. R. Chauvette, J. Org. Chem. 38, 2994 (1973) and J. Amer. Chem. Soc. 96, 4986 (1974), described a process for the preparation of 3-exomethylenecepham compounds and their conversion to 3-hydroxy, 3-methoxy, and 3-halo-3-cephem compounds wherein the substituent group was bonded directly to the carbon in the 3-position of the cephem ring system. Thus, a new class of cephalosporin antibiotics are now known.
As mentioned above, many cephalosporin antibiotics are known wherein the acetoxy group of the acetoxymethyl substituent in the 3-position of the cephalosporanic acid is displaced with a sulfur nucleophile. Exemplary of these compounds are those described by Takano et al. in U.S. Pat. No. 3,516,997, by Ryan in U.S. Pat. No. 3,641,021, and by Clark et al., in U.S. Pat. No. 3,688,203. All of these antibiotics, however, bear the traditional substitution pattern of the cephalosporin antibiotics wherein a methylene group is interposed between the cephem ring and the displacing or substituting group.